Atherosclerosis is a leading cause of morbidity and mortality. The long- term objective of this grant proposal is to evaluate a vaccine that may induce a shift in the lipoprotein profile from an atherogenic one (high LDL, low HDL) to a less-atherogenic one (low LDL, high HDL) and consequently reduce the probability of developing atherosclerosis. This novel vaccine is designed to induce the production of autoantibodies against cholesteryl ester transfer protein (CETP), a naturally occurring serum protein with a role in cholesterol transport. HDL transports cholesterol from peripheral tissues to the liver for excretion. CETP transfers cholesterol from HDL to LDL for recycling back to the peripheral tissues. Anti-CETP antibodies can inhibit CETP activity, reducing cholesterol transfer to LDL. The specific aims of this grant application are to (1) evaluate whether vaccination with this peptide vaccine prevents, delays, or reverses the development of atherosclerosis in rabbits fed a high cholesterol diet either at the same time as vaccination (i.e. animals with developing atherosclerosis) or, (2) evaluate whether vaccination with this peptide vaccine prevents, delays, or reverses the progression of atherosclerosis in rabbits fed a high cholesterol diet before vaccination (i.e. animals with existing atherosclerosis). PROPOSED COMMERCIAL APPLICATION Mortality and morbidity due to atherosclerosis is a major health problem affecting millions of people annually. A risk factor for atherosclerosis is high serum cholesterol, particularly LDL cholesterol, whereas high serum HDL cholesterol is considered a negative risk factor. We have designed a vaccine that should induce lower LDL cholesterol and higher HDL cholesterol in serum, thus reducing the risk of atherosclerosis, and possible reversing existing disease. The market for this vaccine would be extremely large since it would be a significant advance over present therapies.